Thrombosis

Pantep Angchaisuksiri, M.D. Division of Hematology Ramathibodi Hospital

Which test would you do?

1. Protein S, protein C, antithrombin

2. Lupus anticoagulant

3. Cancer screening

4. None

35 y.o. female with right leg swelling for 2 wks History of OC use for 2 months; No FH of VTE

35 y.o. female with right leg swelling for 2 wks History of OC use for 2 months; No FH of VTE

How do you treat this patient? 1. LMWH

2. LMWH/Warfarin

3. NOAC

4. LMWH/NOAC

How long will you treat this patient? 1. 3 months

2. 6 months

3. 12 months

4. Indefinite

35 y.o. female with right leg swelling for 2 wks History of OC use for 2 months; No FH of VTE

Venous Thromboembolism (VTE)

• Clinically important problem:

– death from pulmonary embolism

– morbidity resulting from

• acute event

• recurrent VTE events

• post-thrombotic syndrome

• pulmonary hypertension

Inherited Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden (FVL) Prothrombin 20210A

Acquired Cancer Major surgery Acute medical illness Immobilization Pregnancy Oral contraceptive use Hormonal replacement therapy

Antiphospholipid syndrome (APS) Myeloproliferative neoplasms (MPN) Paroxysmal nocturnal hemoglobinuria (PNH)

Mixed/Unknown Hyperhomocysteinemia High levels of factor VIII High levels of factor IX High levels of factor XI APCR in the absence of FVL

APCR, activated protein C resistance

Risk Factors for Venous Thrombosis

Clinical Characteristics Suggestive of Thrombophilia in Patients with VTE

Thrombosis at a young age (<50yr), especially in association with weak provoking factors (minor surgery, or immobility) or unprovoked VTE Strong family history of VTE (first-degree family members affected at a young age) Recurrent VTE events, especially at a young age* VTE in unusual sites such as splanchnic or cerebral veins†

*The antiphospholipid syndrome must also be considered, but it is not inherited. †Patients with splanchnic vein VTE should be assessed for MPN and PNH.

Risk Categorization of Patients with VTE

• UNPROVOKED

• PROVOKED by a permanent risk factor

(e.g. cancer)

• PROVOKED by a transient, surgical risk factor

• PROVOKED by a transient, non-surgical factor

(e.g. immobilization, acute medical illness, pregnancy,

hormonal therapy)

Provoked VTE Transient

risk factors

Unprovoked

VTE

Provoked VTE Persistent risk factors

e.g. surgery,

trauma, significant immobility, pregnancy

No previous risk factor

for VTE

e.g. active cancer,

antiphospholipid syndrome

Risk of recurrence

Lowest

Kearon C, Ageno W, Cannegieter SC, et al. Journal of Thormbosis and Haemostasis 2016; DOI: 10.1111/jth. 13336.

Risk of Recurrence Depends on Type of VTE Event

Provoked vs. Unprovoked: Risk of Recurrence

1. Baglin T et al, Lancet 2003;362:523–526. 2. Kearon C et al, Chest 2016;149:315–352

Provoked by major RF (Surgery/Trauma)

Nonsurgical RF

Unprovoked

0.15

0.10

0.05

Cum

ulat

ive

prop

ortio

n of

recu

rren

t eve

nts

0.20

Time since event (months) 0 4 8 12 16 20 24

0

Major persistent RF

Selecting Patients with a First VTE for Thrombophilia Testing

No role for testing Determine role of testing Determine role of testing Cerebral vein Splanchnic vein

Test for protein S, protein C,

antithrombin, and APA

Test for inherited

thrombophilia, APA, MPN, and PNH

Consider testing for protein S, protein C,

antithrombin

Consider APA testing in the case of

extensive DVT or PE

Consider APA testing, especially in the case of

arterial or recurrent events

If patient is young and has a strong family

history consider testing for protein S, protein C,

and antithrombin

First VTE

Provoked by strong triggers

Unusual site Unprovoked Provoked by weak triggers in a young patient with strong family history

APA, antiphospholipid antibody

• Influence on duration of anticoagulation therapy

• Possible explanation (for patient and physician) why thrombosis

occurred

Reasons for Thrombophilia Testing

Reasons against Thrombophilia Testing

• Lack of therapeutic consequences even if test positive

• Suboptimal performance of tests (false-positive/negative results)

• Anxiety, if test is positive

• False sense of security that thrombosis risk is low, if test result negative

• Cost of testing

• Lack of impact for asymptomatic first-degree relatives (possible exception is women contemplating estrogen use or pregnancy)

• Impact on ability to obtain life or health insurance

Antiphospholipid Syndrome (APS)

• autoimmune disease

• thrombosis

• pregnancy morbidity

• antiphospholipid antibodies (APA)

Lupus anticoagulants, anti-cardiolipin antibodies and β2glycoprotein I antibodies are antibodies with overlapping specificity but they are not identical antibodies.

A preconference workshop, preceding the Eleventh International Congress on antiphospholipid antibodies (aPL), Sydney consensus conference

One clinical criteria (thrombosis or pregnancy loss) +

One laboratory criteria: anticardiolipin antibodies (no longer required the aCL ELISA to be β2GPI-dependent), lupus anticoagulant, AND anti β2-GPI antibodies [Positive 12 weeks apart]

SYDNEY, 2006

Miyakis S et al. J Thromb Haemost 2006;4:295–306.

CLASSIFICATION CRITERIA

SYDNEY, 2006

I: More than one Laboratory criteria present (any combination) IIa: Lupus Anticoagulant present alone IIb: Anti-cardiolipin antibody present alone IIc: Anti-β2 glycoprotein-I antibody present alone

Miyakis S et al. J Thromb Haemost 2006;4:295–306.

Concept of subclassification: Two different categories of APA

Patients fulfilling classification criteria are put together in clinical studies

Thus APS is diagnosed in the presence of a single positive test*

Classification criteria are often mistaken for diagnostic criteria

* The other two tests either negative or not performed

Definite thrombotic and/or obstetric APS

• Triple positive patients (LAC positive, IgG or IgM aCL> 99th percentile, IgG or IgM ab2GPI> 99th percentile) and proven venous/arterial thrombosis and/or pregnancy loss as of 2006 International consensus statement.

Which test would you do?

1. Protein S, protein C, antithrombin

2. Lupus anticoagulant

3. Cancer screening

4. None

35 y.o. female with right leg swelling for 2 wks History of OC use for 2 months; No FH of VTE

Cancer Screening in Patients with VTE

• Optimal occult cancer screening strategy remains unclear

– Limited screening (History, PE, basic blood work and CXR), and age & gender-specific screening?

• Unknown if detecting these malignancies reduces morbidity, ameliorates quality of life, is cost effective or improves survival

• Clinicians should maintain a low-threshold of suspicion for cancer

Phases of treatment for VTE

1. Kearon et al. Chest 2012;141(2suppl):e419s–e494s; 2. Kearon. J Thromb Haemost 2012;10:507–511.

VKA or other agent† Parenteral*

Initial1

(0–~7 days) Long-term

(~7 days – ~3 months) Extended

(~3 months – indefinite)

Treatment

Secondary prevention Risk

of r

ecur

rent

VTE

Time since starting treatment

Start of treatment and secondary prevention2 Completion of active treatment

*Heparin, LMWH, fondaparinux, thrombolysis. Initial therapy may be with oral rivaroxaban or apixaban. †Includes LMWH and NOACs.

*LMWH, fondaparinux or UFH; †Dabigatran 110 mg BID for aged ≥80 years, concomitant verapamil, or based on individual assessment of thromboembolic/bleeding risk; ‡Edoxaban 30 mg OD for CrCl 15–50 mL/min, weight ≤60 kg, certain concomitant P-gp inhibitors 1. Kearon et al. Chest 2012;141(2 Suppl):e419S–94S; 2. Pradaxa SPC; 3. Lixiana SPC; 4. Xarelto SPC; 5. Eliquis SPC. Current versions available online at: http://www.medicines.org.uk/emc/

Apixaban 10 mg BID 7 days5

Secondary prophylaxis (3 months)

Extended prophylaxis (years)

Rivaroxaban 15 mg BID 21 days4

Parenteral AC* ≥5 days1

Parenteral AC* ≥5 days1

Initial management

Warfarin

Dabigatran 150 mg BID†2

Edoxaban 60 mg OD‡3

Rivaroxaban 20 mg OD

Apixaban 5 mg BID 6 months

Apixaban 2.5 mg BID

Parenteral AC* ≥5 days1

VTE requires acute treatment and prevention of recurrence

Rivaroxaban 10 mg OD

When to Provide Extended Therapy

• Recurrent VTE

• Unprovoked VTE if bleeding risk is not high

• VTE provoked by major persistent risk factors

Which patients can have their dose reduced

All patients except • Recurrent VTE on lower dose

• Active cancer

• High risk thrombophilia

• Concomitant atherothrombosis

No NOACs for:

• Severe renal failure

• Mechanical heart valves

• Triple positive antiphospholipid syndrome

• Concomitant strong inducers/inhibitors of P-glycoprotein or CYP3A4

– >50% decrease/increase in exposure (?)

• (Extreme body weight, poor compliance)

35 y.o. female with right leg swelling for 2 wks History of OC use for 2 months; No FH of VTE

How do you treat this patient? 1. LMWH

2. LMWH/Warfarin

3. NOAC

4. LMWH/NOAC

Risk of VTE recurrence

Risk of bleeding

Need for Extended Anticoagulation Depends on Balance between

Risk of Recurrence off Treatment and Risk of Bleeding on Treatment

Extending Anticoagulant Beyond 3 Months in Patients with VTE: Key Elements

Recurrence risk

Alternatives New oral anticoagulant

Aspirin

Patient preferences and values

Bleeding risk Patient characteristics

Stability of anticoagulation

Consider

Idiopathic, history of VTE, location, gender D-dimer, residual vein thrombosis

Risk of Recurrence – Prediction Scores Vienna Prediction Model

DASH Score HERDOO2

Variables Male sex D-dimer (off AC) PE>prox DVT >distal DVT

Male sex (1 pt) D-dimer (off AC) (2 pt) Age ≤ 50 (1 pt) Hormone use at VTE onset (-2 pt)

Male sex D-dimer (on AC) (1 pt) Age ≥ 65 (1 pt) BMI ≥ 30 (1 pt) PTS signs (1 pt)

Total score 0 to 350 -2 to 4 0 to 6

Annual risk of recurrence

2%-15% (nomogram)

≤1: 1.3% 2: 6.4% ≥3: 12.3%

Women ≤1: 1.6% Women ≥2: 14.1% Men: 13.7%

Eichinger Circulation 2010; Tosetto, JTH 2012; Rodger CMAJ 2008

NO CHANGES UPDATE NEW TOPIC

Risk Factors for Bleeding with Anticoagulant and Estimated Risk of Major Bleeding in Low-, Moderate-, and High-risk Categories

Risk Factors age >65 y age >75 y previous bleeding cancer metastatic cancer renal failure liver failure thrombocytopenia previous stroke diabetes anemia antiplatelet therapy poor anticoagulant control

Comorbidity & reduced functional capacity

recent surgery frequent falls alcohol abuse nonsteroidal anti-inflammatory drug

Categorization of Risk of Bleeding Estimated Absolute Risk of

Major Bleeding low Risk

(0 Risk Factors)

moderate Risk

(1 Risk Factor)

high Risk

(≥2 Risk Factors)

anticoagulation 0-3 mo baseline risk (%) 0.6 1.2 4.8 increased risk (%) 1.0 2.0 8.0 total risk (%) 1.6 3.2 12.8 anticoagulation after first 3 mo baseline risk (%/y) 0.3 0.6 ≥2.5 increased risk (%/y) 0.5 1.0 ≥4.0 total risk (%/y) 0.8 1.6 ≥6.5

Kearon C, et al. Chest 2016

Bleeding Risk Factors

Age

Prior bleeding

Drug interactions

Co-morbidities (kidney, liver, cancer,

anemia, thrombocytopenia)

How long will you treat this patient? 1. 3 months

2. 6 months

3. 12 months

4. Indefinite

35 y.o. female with right leg swelling for 2 wks History of OC use for 2 months; No FH of VTE

How long is long enough?

VTE recurrence after discontinuation of anticoagulant

months

Summary of ACCP 2016 Guidelines: Acute treatment & secondary prevention of VTE

ACCP recommendation Grade of recommendation

Initial anticoagulation

Acute DVT or hemodynamically stable PE

NOAC preferred to LMWH/VKA

2B

PE with hypotension Thrombolytic therapy (systemic rather than catheter-directed unless bleeding risk is high)

2B (2C)

Duration of anticoagulant

Proximal DVT or PE 3 months recommended over shorter duration

1B

First proximal DVT or PE provoked by surgery or other transient risk factor

3 months 1B (2B if low/moderate

bleeding risk) Unprovoked DVT or PE Extended therapy if bleeding risk is

low/moderate 3 months if bleeding risk is high

2B

1B Kearon C et al. Chest 2016;149:315-352.

Treat for 3 months and reassess

Isolated distal DVT

Stop at 3 Months

Reversible provoking factor

Stop at 3 Months

Unprovoked proximal DVT

or PE

Cancer Indefinite therapy or until cancer inactive

High Bleeding Risk OR

Prefers to stop (even if D-dimer was positive)

Stop at 3 Months

Not High Bleeding Risk AND

Prefers to stay on (even if D-dimer was negative)

Indefinite therapy

Second VTE

Indefinite therapy

Negative D-dimer Stay off therapy

(Stop at 3 Months)

Positive D-dimer Restart therapy

(Indefinite therapy)

Duration of Anticoagulant Therapy

Others

Stop and measure D-dimer

after 1 month

What if the patient has cancer?

ACCP 2016 Guidelines

• LMWH is suggested over VKA (2B) and DOAC (2C)

• In those who do not have high risk of bleeding, extended therapy is recommended over 3 months (1B)

• In those who have a high bleeding risk, extended therapy is suggested over 3 months (2B)

Kearon et al. Chest 2016.

NOACs for the Treatment of CAT

*Results reported are 6-month cumulative event rates.

Young A et al, J Clin Oncol 2018: doi:10.1200/JCO.2018.78.8034.

select-d*

HR=1.83 95% CI 0.63–4.96

7% in favour of rivaroxaban

2% in favour of dalteparin

HR=0.43 95% CI 0.19–0.99 Rivaroxaban

Dalteparin

NOACs for the Treatment of CAT

*Results reported are number and percentage of events at 12 months.

Raskob G et al, N Engl J Med 2018;378:615–62.4

Hokusai-VTE-Cancer*

3.4% in favour of edoxaban

3.9% in favour of dalteparin

HR=0.71 95% CI 0.48–1.06;

p=0.09

HR=1.77 95% CI 1.03–3.04;

p=0.04

Edoxaban Dalteparin

DOACs RCT in cancer patients

Bleeding issue: • Significant increase in bleeding risk (HOKUSAI, SELECT-D

and CASSINI)

Mucosa

GI tract

Topical effect on the mucosa NOAC

Topical effect

Systemic anticoagulant effect from NOAC

Incomplete absorption (topical anticoagulant

effect)

Direct caustic effect (eg, tartaric acid in

dabigatran)

Inhibition of mucosal healing

© Medscape, LLC

Conclusions

• VTE is often a chronic condition

• DOACs are at least as effective as VKAs but produce less bleeding

• Availability of usual and lower dose DOAC regimens enable patient-specific choices

• DOACs were recently proved to be at least as effective as LMWH for VTE treatment in cancer patients but were associated with more bleeding